HK1081851A - 1,3-diaza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof - Google Patents

Description

1, 3-diaza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof

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Technical Field

The present invention relates to 1, 3-diaza-dibenzoazulene derivatives of the general formula (I), to their pharmacologically acceptable salts and solvates, to processes and intermediates for the preparation thereof and to their anti-inflammatory effects, in particular to their inhibitory effect on tumor necrosis factor- α (TNF- α) production and on the production of interleukin-1 (IL-1) and to their analgetic action.

Prior Art

There is a lot of literature relating to various 1, 3-diaza-dibenzoazulene derivatives and to processes for their preparation. It is well known that 1, 3-diazadibenzoazulene derivatives and salts thereof have anti-inflammatory effects and represent a new class of compounds having such effects. Thus, in a series of patents (U.S. Pat. No. 3,711,489, U.S. Pat. No. 3,781,294 and CA 967,573) a process for the preparation of dibenzoazulenes of imidazoles carrying different substituents at the 2-position, such as trifluoromethyl, pyridyl, naphthyl, phenyl and substituted phenyl, is disclosed. Furthermore, the corresponding imidazoles with alkylthio substituents in the 2-position have a similar effect (U.S. Pat. No. 4,198,421; EP 372,445 and WO 9,118,885).

It is also known that 1-thia-dibenzoazulenes carrying aminoalkoxy substituents on the thiophene ring have anti-inflammatory effects (WO 01/878990).

According to our knowledge and available literature data, dibenzoazulenes of imidazoles bearing hydroxyalkyl, alkoxy, aminoalkoxy, carboxyl, acetyl or amino groups on the imidazole ring, which represent the object of the present invention, have not been prepared or disclosed so far. It is not understood that such compounds may have anti-inflammatory and/or analgesic effects, which effects also represent an object of the present invention.

TNF- α is defined as a serum factor that is endotoxin induced and causes tumor necrosis in vitro and in vivo (Carswell EA et al, Proc. Natl. Acad. Sci. U.S.A., 1975, 72: 3666- > 3670). In addition to anti-tumor effects, TNF- α has many other biological effects that are important in homeostasis and pathophysiological conditions. The main sources of TNF-alpha are monocyte-macrophages, T-lymphocytes and mast cells.

The discovery that anti-TNF-. alpha.antibodies (cA2) have therapeutic effects on patients with Rheumatoid Arthritis (RA) (Elliott M et al, Lancet (Lancet), 1994, 344: 1105-1110) has led to an increased interest in finding new TNF-. alpha.inhibitors that can act as effective agents for RA. Rheumatoid arthritis is an autoimmune chronic inflammatory disease characterized by irreversible pathological changes in the joints. In addition to RA therapy, TNF- α antagonists may be used in a number of pathological conditions and diseases such as spondylitis, osteoarthritis, gout and other arthritic diseases, sepsis, septic shock, toxic shock syndrome, atopic dermatitis, contact dermatitis, psoriasis, glomerulonephritis, lupus erythematosus, scleroderma, asthma, cachexia, chronic obstructive non-disease, congestive cardiac arrest, insulin resistance, pulmonary fibrosis, multiple sclerosis, crohn's disease, ulcerative colitis, viral infections and AIDS.

Some evidence of the biological importance of TNF- α was obtained by in vivo experiments in mice in which the mouse gene for TNF- α or its receptor was inactivated. Such animals are resistant to collagen-induced arthritis (Mori L et al, J.Immunol., 1996, 157: 3178-. In animal experiments with increased levels of TNF-alpha, chronic inflammatory polyarthritis similar to RA occurs (Georgopoulos S et al, J.Inflamm., 1996, 46: 86-97; Keffer J et al, J.European Association of molecular biology (EMBO J.), 1991, 10: 4025-one 4031) and its pathological picture can be alleviated using inhibitors of TNF-alpha production. Treatment of such inflammatory and pathological conditions typically involves administration of non-steroidal anti-inflammatory drugs and in more severe cases gold salts, D-penicillamine or methotrexate. Said drugs act symptomatically, but they do not bring the pathological condition to a halt. The new approaches in rheumatoid arthritis therapy are based on drugs such as tenidap, leflunomide, cyclosporin, FK-506 and on biomolecules that counteract the effects of TNF-a. Commercially available etanercept (Enbrel, Immunex/Wyeth), fusion proteins of the instant TNF-alpha receptor and infliximab (Remicade, Centocor), chimeric monoclonal human and mouse antibodies, currently exist. Etanercept and infliximab were registered for crohn's disease therapy in addition to RA therapy (exp. opin. invest. drugs, 2000, 9: 103).

In addition to inhibiting TNF- α secretion, inhibition of IL-1 secretion is also of paramount importance in optimal RA therapy, since IL-1 is an important cytokine in cell regulation and immune regulation as well as pathophysiological conditions such as inflammation (Dinarello CA et al, review of infectious diseases (Rev. infection. disease), 1984, 6: 51). The well-known biological activities of IL-1 are: activation of T-cells, induction of elevated temperatures, stimulation of prostaglandin or collagenase secretion, chemotaxis of neutrophils and a decrease in plasma iron levels (Dinarello CA, J.clinical Immunology, 1985, 5: 287). Two receptors to which IL-1 can bind are well known: IL-1RI and IL-1 RII. IL-1RI transduces intracellular signals, whereas IL-1RII, although it may be located on the cell surface, does not transduce intracellular signals. Since IL1-RII binds to IL-1 and IL1-RI, it can act as a negative regulator of IL-1 action. In addition to this signal transfer regulatory mechanism, another natural antagonist of the IL-1 receptor, IL-1ra, is present in cells. This protein binds to IL-1RI, but does not stimulate it. IL-1ra in termination of IL-1 stimulated signal transfer efficiency is not high and its concentration is greater than IL-1 concentration 500 times in order to make the signal transfer interruption. Recombinant human IL-1RA (Amgen) (Bresenihan B et al, rheumatoid arthritis (Arthrit. Rheum.), 1996, 39: 73) was tested clinically and the results obtained indicated an improvement in clinical images of RA patients over placebo. These results demonstrate the importance of inhibiting IL-1 action in the treatment of diseases in which IL-1 production is disturbed, such as RA. Because of the synergistic effects of TNF-alpha and IL-1, dual inhibitors of TNF-alpha and IL-1 can be used to treat disorders and diseases associated with increased secretion of TNF-alpha and IL-1.

Technical scheme of the invention

The present invention relates to compounds of 1, 3-diaza-dibenzoazulene of the general formula I:

wherein

X may be CH₂Or heteroatoms such as O, S, S (═ O), S (═ O)₂Or NR^aWherein R is^aIs hydrogen or a protecting group;

y and Z independently of one another represent one or more identical or different substituents attached to any available carbon atom and may be halogen, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, halo-C₁-C₄Alkyl, hydroxy, C₁-C₄Alkoxy, trifluoromethoxy, C₁-C₄Alkanoyl, amino-C₁-C₄Alkyl, N- (C)₁-C₄Alkyl) amino, N-di (C)₁-C₄Alkyl) amino, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, carboxy, C₁-C₄Alkoxycarbonyl, cyano, nitro;

R¹can be halogen, hydroxyl, C₁-C₇Alkoxy, aryloxy, amino, N- (C)₁-C₇Alkyl) amino, N-di (C)₁-C₇Alkyl) amino, (C)₁-C₇Alkyl) amino, amino-C₁-C₇Alkoxy radical, C₁-C₇Alkanoyl, aroyl, C₁-C₇Alkanoyloxy, carboxy, optionally substituted C₁-C₇Alkoxycarbonyl or aryloxycarbonyl, carbamoyl, N- (C)₁-C₇Alkyl) carbamoyl, N-di (C)₁-C₇Alkyl) carbamoyl, cyano, nitro;

or a substituent of formula II:

wherein

R³And R⁴Can be hydrogen and C simultaneously or independently of each other₁-C₄-alkyl, aryl or together with N have the meaning of optionally substituted heterocycle or heteroaryl;

m represents an integer of 1 to 3;

n represents an integer of 0 to 3;

Q₁and Q₂Independently of one another, represents oxygen, sulfur or the following groups:

wherein the substituents are

y₁And y₂May be independently of one another hydrogen, halogen, optionally substituted C₁-C₄Alkyl or aryl, hydroxy, C₁-C₄Alkoxy radical, C₁-C₄Alkanoyl, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, cyano, nitro or form a carbonyl or imino group with one another;

R²with hydrogen, optionally substituted C₁-C₇Alkyl or aryl or protective group meanings: formyl radical, C₁-C₇Alkanoyl radical, C₁-C₇Alkoxycarbonyl, arylalkoxycarbonyl, aroyl, arylalkyl, C₁-C₇An alkylsilyl group.

The term "halogen (halo)", "halogen (hal)" or "halogen (halogen)" refers to a halogen atom, which may be fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to an alkyl group having the meaning of a group derived from an alkane, which group may be linear, branched or cyclic or a combination of linear and branched groups as well as a combination of branched and cyclic groups. Preferred straight or branched chain alkyl groups are: such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. Preferred cycloalkyl groups are: for example cyclopentyl or cyclohexyl.

The term "haloalkyl" refers to an alkyl group that must be substituted with at least one halogen atom. The most common haloalkyl groups are: for example chloromethyl, dichloromethyl, trifluoromethyl or 1, 2-dichloropropyl.

The term "alkenyl" refers to an alkenyl group having the meaning of a hydrocarbon group which may be straight chain, branched chain or cyclic or a combination of straight and branched groups or a combination of branched and cyclic groups, but which contains at least one carbon-carbon double bond. The most common alkenyl groups are ethenyl, propenyl, butenyl or cyclohexenyl.

The term "alkynyl" refers to an alkynyl group having the meaning of a hydrocarbyl group that is straight or branched chain and contains at least one and at most two carbon-carbon triple bonds. The most common alkynyl groups are: for example ethynyl, propynyl or butynyl.

The term "alkoxy" refers to a straight or branched chain alkoxy group. Examples of such groups are methoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy.

The term "aryl" refers to groups having the meaning of aromatic rings, such as phenyl, as well as fused aromatic rings. The aryl group contains one ring with at least 6 carbon atoms or two rings with a total of 10 carbon atoms and with an optional double (resonant) bond between the carbon atoms. The most commonly used aryl groups are: such as phenyl or naphthyl. In general, the aryl group may be bonded directly or through C via any available carbon atom₁-C₄An alkylene group, such as methylene or ethylene, is attached to the remainder of the molecule.

The term "heteroaryl" refers to a group having the meaning of an aromatic and partially aromatic monocyclic or bicyclic group containing 4 to 12 atoms, at least one of which is a heteroatom such as O, S or N, and the available nitrogen or carbon atoms being the group either through a direct bond or through C as defined above₁-C₄Alkylene and remainder of moleculeA discrete binding site. Examples of this type are thiophenyl, pyrrolyl, imidazolyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, quinolinyl or triazinyl.

The term "heterocycle" refers to a 5-or 6-membered fully saturated or partially unsaturated heterocyclic group containing at least one heteroatom, such as O, S or N, and the available nitrogen or carbon atom is the group either through a direct bond or through C as defined above₁-C₄The point of attachment of the alkylene group to the remainder of the molecule. The most common examples are morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazinyl or imidazolyl.

The term "alkanoyl" refers to straight chain acyl groups such as formyl, acetyl or propionyl.

The term "aroyl" refers to an aromatic acyl group, such as benzoyl.

The term "optionally substituted alkyl" refers to an alkyl group that may be optionally further substituted with one, two, three or more substituents. Such substituents may be halogen atoms (preferably fluorine or chlorine), hydroxy groups, C₁-C₄Alkoxy (preferably methoxy or ethoxy), thiol, C₁-C₄Alkylthio (preferably methylthio or ethylthio), amino, N- (C)₁-C₄) Alkylamino (preferably N-methylamino or N-ethylamino), N-di (C)₁-C₄-alkyl) -amino (preferably dimethylamino or diethylamino), sulfonyl, C₁-C₄Alkylsulfonyl (preferably methylsulfonyl or ethylsulfonyl), sulfinyl, C₁-C₄Alkylsulfinyl (preferably methylsulfinyl).

The term "optionally substituted alkenyl" refers to alkenyl groups which may optionally be further substituted by one, two or three more halogen atoms. Such substituents may be: for example 2-chloroethenyl, 1, 2-dichlorovinyl or 2-bromo-propen-1-yl.

The term "optionally substituted aryl, heteroaryl or heterocycle" means that it may optionally be further substituted by one or moreAryl, heteroaryl or heterocyclyl substituted with two substituents. The substituent may be halogen (preferably chlorine or fluorine), C₁-C₄Alkyl (preferably methyl, ethyl or isopropyl), cyano, nitro, hydroxy, C₁-C₄Alkoxy (preferably methoxy or ethoxy), thiol, C₁-C₄Alkylthio (preferably methylthio or ethylthio), amino, N- (C)₁-C₄) Alkylamino (preferably N-methylamino or N-ethylamino), N-di (C)₁-C₄-alkyl) -amino (preferably N, N-dimethylamino or N, N-diethylamino), sulfonyl, C₁-C₄Alkylsulfonyl (preferably methylsulfonyl or ethylsulfonyl), sulfinyl, C₁-C₄Alkylsulfinyl (preferably methylsulfinyl).

When X has NR^aAnd R is^aWith the meaning of a protecting group, R^aRefers to such groups as alkyl (preferably methyl or ethyl), alkanoyl (preferably acetyl), alkoxycarbonyl (preferably methoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl (preferably benzyloxycarbonyl), aroyl (preferably benzoyl), aralkyl (preferably benzyl), alkylsilyl (preferably trimethylsilyl) or alkylsilylalkoxyalkyl (preferably trimethylsilylethoxymethyl).

When R is³And R⁴When taken together with N has the meaning of heteroaryl or heterocyclic, this means that such heteroaryl or heterocyclic contains at least one carbon atom substituted by a nitrogen atom through which the group is attached to the remainder of the molecule.

Examples of such groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, imidazol-1-yl or piperazin-1-yl.

The term "pharmaceutically suitable salts" refers to salts of compounds of formula I and includes: for example with C₁-C₄Salts of alkyl halides (preferably methyl bromide, methyl chloride) (quaternary ammonium salts), salts with inorganic acids (hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric or phosphoric acid) or with organic acids (tartaric, acetic, citric acid)Acid, maleic acid, lactic acid, fumaric acid, benzoic acid, succinic acid, methanesulfonic acid, or p-toluenesulfonic acid).

Certain compounds of formula I may form salts with organic or inorganic acids or bases and are also included in the present invention.

Solvates which may be formed from compounds of formula I or salts thereof (most commonly hydrates) are also objects of the present invention.

Depending on the nature of the particular substituents, the compounds of the general formula I may have geometric isomers and one or more chiral centers, whereby enantiomers or diastereomers may be present. The invention also relates to such isomers and mixtures thereof, including racemates.

The invention also relates to all possible tautomeric forms of the specific compounds of the general formula I.

Another object of the present invention is a process for the preparation of a compound of formula I, which process comprises the following steps:

a) for compounds of the formula I, in which R is¹Having the meaning of CHO, formylating a compound of the general formula III:

b) for compounds of the formula I, in which Q₁Having the meaning of-O-, reacting an alcohol of the formula IV with a compound of the formula V,

wherein the structural formula of formula IV is as follows:

wherein the formula of formula V is as follows:

wherein L is¹Having the meaning of a leaving group;

c) for compounds of the formula I, in which Q₁Has the meaning of-O-, -NH-, -S-or-C ≡ C-,

reacting a compound of formula IVa with a compound of formula Va,

wherein the formula of formula IVa is as follows:

wherein L has the meaning of a leaving group;

wherein the formula of formula Va is as follows:

d) for compounds of the formula I, in which Q₁Having the meaning of-O-, -NH-or-S-,

reacting a compound of formula IVb with a compound of formula V,

wherein the formula of formula IVb is as follows:

in the compounds of the formula V, L has the meaning of a leaving group;

e) for compounds of the formula I, in which Q₁Has the meaning of-C ═ C-,

reacting a compound of formula IVb, in which Q is Q, with a phosphonium ylide₁Has the meaning of carbonyl.

The preparation method comprises the following steps:

a) the compounds of formula I can be obtained by the following steps:formylating a compound of formula III in which R is present in²Having the meaning of a protecting group, in the compounds of the formula I, R¹Having the meaning of CHO, followed by the addition of N, N-dimethylformamide and the reaction at room temperature. The product is isolated and purified by crystallization or silica gel column chromatography.

As starting materials for the preparation of compounds of formula III, the corresponding dibenzo-azulenes of formula IIIa are already known or prepared by the methods disclosed for the preparation of similar compounds:

thus, for example, compounds of formula III may be prepared from α -diketo dibenzo-oxepines (oxepines) or dibenzo-thiepines (thiepines) as starting materials. By the action of the aldehyde and ammonium acetate on the α -diketone, cyclization occurs and a fused imidazole ring is formed. The unsubstituted imidazole ring is formed by reaction of paraformaldehyde. Similar reaction procedures have been disclosed in the literature (Lombardino J et al, J. Heterocyclic Chem., 1974, 11: 17-21). Protection of the free NH-group of the compound of formula IIIa by the action of the compound of formula IIIb (WO 98/47892) forms compound III as a mixture of 1-and 3-substituted isomers:

R²-L²

IIIb

wherein L is²With the meaning of a leaving group, such as halogen (most commonly chlorine or bromine). The reaction is carried out in an organic solvent such as dimethylsulfoxide, tetrahydrofuran, benzene or toluene, to which a strong base such as sodium hydride is added, and the temperature is raised from 50 to 150 ℃ during the reaction for 1 to 5 hours. Can separate coarseThe product is purified by recrystallization or silica gel column chromatography.

b) The compounds of the general formula I of the process according to the invention can be prepared by reacting alcohols of the general formula IV with compounds of the general formula V, where L¹Having the meaning of a leaving group which may be a halogen atom (most commonly bromine, iodine or chlorine) or a sulfonyloxy group (most commonly a trifluoromethylsulfonyloxy or p-toluenesulfonyloxy group). The condensation reaction may be carried out according to the methods disclosed for the preparation of analogous compounds (Menozzi G et al, J.HeterocyclicChem., 1997, 34: 963-968 or WO 01/87890). The reaction is carried out at a temperature of 20 ℃ to 100 ℃ for 1 to 24 hours in a two-phase system (preferably with 50% NaOH/toluene) in the presence of a phase transfer catalyst (preferably benzyltriethylammonium chloride, benzyltriethylammonium bromide, cetyltrimethyl bromide). After work-up of the reaction mixture, the product formed is isolated by recrystallization or silica gel column chromatography.

Starting materials of alcohols of the general formula IV, in which R is¹With the meaning of suitable functional groups. Thus, for example, the alcohols of the formula IV can be obtained by reduction of aldehydes, carboxyl groups or alkoxycarbonyl groups (for example methoxycarbonyl or ethoxycarbonyl groups) using metal hydrides, such as lithium aluminium hydride or sodium borohydride. In addition, the alcohols of the general formula IV can be prepared by hydrolysis of the corresponding esters in basic or acidic medium.

The starting compounds of the formula V are known or can be prepared according to the methods disclosed for the preparation of analogous compounds.

c) The compounds of the process of the invention can be prepared by reacting a compound of formula I, formula IVa, wherein L has the above pair L, with a compound of formula Va¹The meaning of said leaving group, in the compounds of the formula Va, Q₁Has the meaning of oxygen, nitrogen, sulphur or-C ≡ C-. The most suitable condensation reaction is a nucleophilic substitution reaction on a saturated carbon atom as disclosed in the literature.

Can be prepared by using the method as disclosed in the literature, using the commonly used halogenChemicals (hydrobromic acid, PBr)₃、SOCl₂Or PCl₅) Halogenation (e.g. bromination or chlorination) of compound IV of formula IV gives the starting compound of formula IVa (most commonly the halide). The compounds obtained may be isolated or used without isolation as suitable intermediates for the preparation of the compounds of the general formula I.

The starting compounds of formula Va are either known or prepared according to the methods disclosed for the preparation of analogous compounds.

d) The compounds of the formula I, wherein Q is₁Having the meaning of-O-, -NH-or-S-, wherein L¹Having the meaning of the leaving group described above. The reaction can be carried out under the reaction conditions disclosed in process b) or under the nucleophilic substitution reaction conditions disclosed in the literature.

The starting alcohols and amine thiols can be obtained by reacting compound IVa with water, ammonia water or hydrogen sulfide according to the methods disclosed in the literature.

e) Alcohols of structure IV can be oxidized to the corresponding compounds of formula IVb, where Q₁Has the meaning of carbonyl and can be further chain extended by reaction with the corresponding ylide reagent and form an alkenyl substituent with a carbonyl or ester group as disclosed in HR patent application 20000310.

In addition to the above reactions, the compounds of formula I may be prepared by converting other compounds of formula I, and it is to be understood that the invention also encompasses such compounds and methods. Specific examples of modifying the functional groups are reacting the aldehyde groups with selected phosphorus inner salts, chain extending and further chain extending by reaction with the corresponding ylide reagent and forming alkenyl substituents with carbonyl or ester groups as disclosed in HR patent application 20000310. These reactions are carried out in a solvent such as benzene, toluene or hexane at elevated temperature (most commonly boiling temperature).

By reacting a compound of formula IVa with 1-alkyne in a basic medium, such as sodium amide in aqueous ammoniaTo give compounds of the general formula I, in which Q₁is-C.ident.C-. The reaction conditions for this process are disclosed in the literature. Under similar reaction conditions (nucleophilic substitution), various ether, thioether, or amine derivatives can be prepared.

Formylation of compounds of formula I by such methods as Vilsmeier acylation or reaction of N-BuLi with N, N-dimethylformamide is another general example of conversion. The reaction conditions for these processes are well known in the literature.

Carboxyl group-containing compounds can be prepared by hydrolysis of compounds of formula I containing nitrile, amide or ester groups, which are intermediates for the preparation of other compounds bearing new functional groups, such as: such as esters, amides, halides, anhydrides, alcohols or amines.

Oxidation or reduction reactions have the possibility to further change the substituents on the compounds of the general formula I. The most commonly used oxidizing agents are peroxides (hydrogen peroxide, m-chloroperbenzoic acid or benzoyl peroxide) or permanganate, chromate or perchlorate ions. Thus, for example, an aldehyde group is formed by oxidation of an alcohol group with pyridine dichromate (pyridine dichromate) or pyridine chlorochromate, which can be converted into a carboxyl group by further oxidation. Oxidation of a compound of formula I, wherein R is¹Having the meaning of alkyl, to give the corresponding carbonyl derivatives.

Alkylsulfinyl or alkylsulfonyl may be prepared by selective oxidation of an alkylthio group.

The amino compound can be prepared by reducing a compound having a nitro group. The reaction is carried out by conventional catalytic hydrogenation or electrochemically. The alkenyl substituents may be converted to alkyl ketones or the nitrile groups may be converted to aminoalkyl groups by catalytic hydrogenation using palladium on carbon.

Different substituents of the aromatic structure can be introduced on the compounds of the formula I by standard substitution reactions or by modification of the individual functional groups which are customarily employed. Examples of such reactions are aromatic substitution, alkylation, halogenation, hydroxylation and oxidation or reduction of substituents. Reagents and reaction conditions are known from the literature. Thus, for example, the nitro group is introduced by aromatic substitution in the presence of concentrated nitric acid and sulfuric acid. The acyl or alkyl group can be introduced by using an acyl halide or an alkyl halide. The reaction is carried out in the presence of a Lewis acid, such as aluminum trichloride or ferric trichloride, and under Friedel-crafts reaction conditions. By reduction of the nitro group to give an amino group, which is converted to the appropriate starting group by diazotization, it may be substituted with one of the following groups: H. CN, OH and Hal.

In order to prevent unwanted interactions in chemical reactions, it is often necessary to protect certain groups, such as: such as hydroxyl, amino, sulfur or carboxyl. For this purpose, a number of protecting groups can be used (Green TW, Wuts PGH, a protecting group from organic Synthesis, John Wiley and Sons, 1999) and their selection, use and elimination are conventional methods in chemical Synthesis.

Common protecting groups for amino or alkylamino are the following groups: such as, for example, alkanoyl (acetyl), alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl); arylmethoxycarbonyl (benzyloxycarbonyl), aroyl (benzoyl) or alkylsilyl (trimethylsilyl or trimethylsilylethoxymethyl). The conditions for removing the protecting group depend on the choice of the group and its characteristics. Thus, for example, acyl groups such as alkanoyl, alkoxycarbonyl or aroyl groups can be eliminated by hydrolysis in the presence of a base (sodium hydroxide or potassium hydroxide); t-butoxycarbonyl or alkylsilyl (trimethylsilyl) groups may be eliminated by treatment with a suitable acid (hydrochloride, sulfuric, phosphoric or trifluoroacetic acid), while arylmethoxycarbonyl (benzyloxycarbonyl) groups may be eliminated by hydrogenation using a catalyst such as palladium on carbon.

Salts of the compounds of formula I can be prepared by generally known methods, for example by reacting a compound of formula I with the corresponding base or acid in a suitable solvent or solvent mixture, for example ethers (diethyl ether) or alcohols (ethanol, propanol or isopropanol).

Another object of the present invention relates to the use of the compounds of the present invention in the treatment of inflammatory diseases and conditions, in particular of all diseases and conditions induced by excessive secretion of TNF-alpha and IL-1.

An effective dose of an inhibitor of the production of cytokines or inflammation mediators, which is the object of the present invention, or a pharmacologically acceptable salt thereof, can be used for the manufacture of a medicament for the treatment and prevention of any pathological condition or disease induced by unregulated production of cytokines or inflammation mediators.

More particularly, the invention relates to effective dosages of TNF- α inhibitors that can be determined by conventional methods.

Furthermore, the present invention relates to pharmaceutical formulations comprising an effective non-toxic dose of a compound of the present invention and a pharmacologically acceptable carrier or solvent.

The preparation of the pharmaceutical formulation may include blending, granulating, tableting, and dissolving the components. The chemical carrier may be a solid or a liquid. The solid carrier can be lactose, sucrose, talc, gelatin, agar, pectin, magnesium stearate, fatty acid, etc. The liquid carrier may be: syrup; oils, such as olive oil, sunflower oil or soybean oil; water, and the like. Similarly, the carrier may also contain ingredients which provide sustained release of the active ingredient, such as, for example, glyceryl stearate or glyceryl distearate. Various forms of pharmaceutical preparations may be used. Tablets, hard capsules, powders or granules which can be administered orally in capsule form can be prepared by using solid carriers. The amount of solid carrier may vary, but is primarily from 25mg to 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution, such as an ampoule, or nonaqueous liquid suspension.

The compounds of the present invention may be administered orally, parenterally, topically, intranasally, intrarectally, and intravaginally. Parenteral routes herein refer to intravenous, intramuscular, and subcutaneous administration. Suitable formulations of the compounds of the present invention may be used for the prevention and treatment of inflammatory diseases induced by unregulated cytokine or inflammation mediator, primarily overproduction of TNF- α. They include: such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic pathologies and diseases, eczema, psoriasis and other skin diseases, inflammatory eye diseases, crohn's disease, ulcerative colitis and asthma.

The inhibition of TNF-alpha and IL-1 secretion by the compounds of the invention was determined by the following in vitro and in vivo experiments:

measurement of TNF-alpha and IL-1 secretion in human peripheral blood mononuclear cells in vitro

By using Ficoll-Paque^TMPlus (Amersham-Pharmacia) heparinized whole blood after PBMC separation human Peripheral Blood Mononuclear Cells (PBMC) were prepared. For the determination of TNF-. alpha.levels, a total volume of 200. mu.l of 3.5-5X 10 was added in RPMI 1640 medium in microtiter plates (96-well, Falcon) with a flat bottom⁴Each cell was cultured for 18-24 hours, to which 10% FBS (fetal bovine serum, Biowhittaker) previously inactivated, 100 units/ml penicillin, 100mg/ml streptomycin and 20mM HEPES (GIBCO) were added at 56 ℃/30 minutes. Contacting the cells with a solution containing 5% CO at 37 ℃ and 90% humidity₂The gas is kept warm. In the negative control, cells were cultured in medium (NC) only, whereas in the positive control TNF-. alpha.secretion was induced by addition of 1ng/ml lipopolysaccharide (LPS, E.coli serotype 0111: B4, SIGMA) (PC). The effect of the test substances on TNF-. alpha.secretion was investigated after their addition to cell cultures stimulated with LPS (TS). By ELISA procedure, according to the manufacturer (R)&D Systems) to determine the level of TNF-alpha in the cell supernatant. The test sensitivity was < 3pg/ml TNF-. alpha.. By ELISA procedure (R) under the same conditions and in assays using the same number of cells and the same concentration of stimulus&D Systems) to determine IL-1 levels. Percent inhibition of TNF- α or IL-1 production was calculated by the following equation: inhibition [% 1- (TS-NC)/(PC-NC)]*100。

Will IC₅₀Values are defined as the concentration of the substance that inhibits 50% of TNF-. alpha.production.

IC exhibiting a concentration of 20. mu.M or less than 20. mu.M₅₀The compound of (3) has activity.

Determination of TNF-alpha and IL-1 secretion in mouse peritoneal macrophages in vitro

To obtain peritoneal macrophages, 8-12 week old male Balb/C mouse strains were injected intraperitoneally with 300 μ g zymosan (SIGMA) in Phosphate Buffered Saline (PBS) in a total volume of 0.1 ml/mouse. After 24 hours, mice were euthanized according to Laboratory Animal Welfare Act. The abdominal cavity was washed with sterile physiological solution (5 ml). The peritoneal macrophages obtained were washed twice with sterile physiological solution and, after final centrifugation (350g/10 min), were suspended in RPMI 1640 to which a portion of 10% FBS was added. To determine TNF-alpha secretion, a total volume of 200. mu.l of 5X 10 was applied in RPMI 1640 medium in microtiter plates (96-well, Falcon) with a flat bottom⁴Each cell was cultured for 18-24 hours, and heat-inactivated 10% fetal bovine serum (FBS, Biowhittaker), 100 units/ml penicillin, 100mg/ml streptomycin, 20mM HEPES and 50. mu.M 2-mercaptoethanol (both from GIBCO) were added thereto at 56 ℃/30 minutes. Contacting the cells with a solution containing 5% CO at 37 ℃ and 90% humidity₂The gas is kept warm. In the negative control, cells were cultured in medium (NC) only, whereas in the positive control TNF-. alpha.secretion was induced by addition of 10ng/ml lipopolysaccharide (LPS, E.coli serotype 0111: B4, SIGMA) (PC). The effect of the substances on TNF-alpha secretion was investigated after their addition to cell cultures stimulated with LPS (TS). By the action on TNF-alpha and IL-1 (R)&D Systems, Biosource) the levels of TNF-. alpha.and IL-1 in the cell supernatants were determined by a specific ELISA procedure. By ELISA procedure (R) in the same assay as for TNF-. alpha.&D Systems) to determine IL-1 levels. Percent inhibition of TNF- α or IL-1 production was calculated by the following equation: inhibition [% 1- (TS-NC)/(PC-NC)]*100。

Will IC₅₀Values are defined as the concentration of the substance that inhibits 50% of TNF-. alpha.production.

IC exhibiting concentrations of 10. mu.M or less than 10. mu.M₅₀The compound of (3) has activity.

In vivo model of LPS-induced TNF-alpha or IL-1 hypersecretion in mice

TNF-. alpha.or IL-1 secretion in mice was induced according to the published methods (Badger AM et al, J.Pharmac.env.Therap., 1996, 279: 1453-1461). Male Balb/C animals, 8-12 weeks old, divided into groups of 6-10 animals were used. Animals were treated with oral dosing with solvent alone (in negative and positive controls) or the substance solution was given 30 minutes prior to treatment with LPS (E.coli serotype 0111: B4, Sigma) at a dose of 1-25. mu.g/animal. Animals were euthanized after 2 hours by intraperitoneal injection of roumpun (bayer) and ketamine hydrochloride (Ketanest) (Parke-Davis).

Blood samples from each animal were taken into Vacutainer tubes (Becton Dickinson) and plasma was isolated according to the manufacturer's instructions. TNF-. alpha.levels in plasma were determined by ELISA procedures (Biosource, R & D Systems) according to the manufacturer's instructions. The test sensitivity was < 3pg/ml TNF-. alpha.. IL-1 levels were determined by ELISA procedures (R & D Systems). Percent inhibition of TNF- α or IL-1 production was calculated by the following equation:

inhibition [% 1- (TS-NC)/(PC-NC) ]. 100.

Compounds exhibiting 30% or more than 30% inhibition of TNF- α production at a dose of 10mg/kg are active.

Writhing test for analgesic activity

In this experiment, pain was induced by injecting a stimulant, most commonly acetic acid, into the abdominal cavity of mice. Animals have a characteristic writhing response with the name of the test assigned (Collier HOJ et al, Pharmac. Chemothers., 1968, 32: 295-310; Fukawa K et al, J. Pharmac. meth., 1980, 4: 251-259; Schweizer A et al, Effect of active Agents (Agents Actions), 1988, 23: 29-31). This assay readily determines the analgesic activity of the compounds. The method comprises the following steps: male Balb/C mice (Charles River, Italy) 8-12 weeks old were used. The control group received orally administered methylcellulose 30 minutes before intraperitoneal administration of 0.6% strength acetic acid, while the test group received orally administered standard (acetylsalicylic acid) or test substance in methylcellulose 30 minutes before intraperitoneal administration of 0.6% acetic acid (0.1 ml/10g volume). The mice were placed individually in glass funnels and the number of writhes was recorded for each animal over 20 minutes. The percentage of writhing inhibition was calculated according to the following equation: inhibition [% inhibition ] (% of twists in control-mean of number of twists in test group)/number of twists in control 100.

Compounds exhibiting analgesic activity such as acetylsalicylic acid or better than its activity are active.

In vivo model of LPS-induced mouse shock

8-12 week old Male Balb/C mice (Charles River, Italy) were used. LPS from Serratia autohesia (Serratiemarchessans) (Sigma, 1-6136) was isolated by dilution with sterile physiological solution. LPS injections were first given intradermally at a dose of 4. mu.g/mouse. After 18-24 hours, 200. mu.g/mouse of LPS was administered intravenously. The control group received two LPS injections as described above. The test groups received the orally administered substance half an hour prior to each administration of LPS. Survival was observed after 24 hours.

The substance has an activity with a survival rate of 40% or more than 40% at a dose of 30 mg/kg.

The compounds from examples 8 and 9 show activity in at least two studies, however, these results represent only an explanation of the biological activity of the compounds and should not be construed as limiting the invention in any way.

Preparation method and examples

The invention is illustrated by the following examples, which are not intended to limit the invention in any way.

Example 1

1-methyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde (15; Table I)

To the compound at-78 ℃ under stirring5(1.8mmole) in dry tetrahydrofuran (10.0ml) was added a 1.6M solution of n-butyllithium in hexane (5.4 mmole). The reaction mixture was stirred at-78 ℃ for 15 minutes, then dry N, N-dimethylformamide (4.5mmole) was added and the reaction mixture was stirred at room temperature for another 1 hour, after which the system was diluted with water and extracted with ethyl acetate. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the oily product was isolated.

The following compounds were prepared according to the above procedure starting from compounds 6-14:

1-methyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

1-phenethyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde (table I, compounds 16-24).

Example 2

3- (1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -acrylic acid methyl ester (25; Table I)

To a solution of compound 18(0.82mmole) in toluene (25.0ml) was added methyl (triphenylphosphoranilide) -acetate (0.82mmole) with stirring. The reaction mixture was heated and refluxed for 3 hours with stirring, then the system was cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the crystalline product was isolated.

TABLE I

Compound (I)	X	Y	Z	R1	R2	MS(m/z)	1H NMR(ppm，CDCl3)
								15	O	H	H	CHO	Me	MH+277.4	9.97(s，1H)，7.94-7.29(m，8H)，4.22(s，3H)
16	S	H	H	CHO	Me	MH+293.1	10.00(s，1H)，7.95-7.33(m，8H)，4.14(s，3H)
								17	O	H	H	CHO	(CH2)2Ph	MH+367.5	9.94(s，1H)，7.92-7.16(m，13H)，4.89(t，2H)，3.14(t，2H)
18	S	H	H	CHO	(CH2)2Ph	MH+383.1	9.92(s，1H)，7.93-7.04(m，13H)，5.13-4.66(m，2H)，3.07-2.89(m，2H).
								19	O	H	H	CHO	SEMa	MNa+415.2	10.07(s，1H)，8.07-7.29(m，8H)，5.89(s，2H)，3.88(t，2H)，1.03(t，2H)，0.03(s，9H)
20	S	H	H	CHO	SEM	MNa+431.1	10.03(s，1H)，7.95-7.34(m，8H)，6.11-5.41(m，2H)，3.86-3.66(m，2H)，1.00-0.89(m，2H)，0.03(s，9H)
								21	O	5-Cl	H	CHO	SEM	MNa++MeOH481.1	9.99(s，1H)，8.08-7.23(m，7H)，5.88(s，2H)，3.87(t，2H)，1.03(t，2H)，0.03(s，9H)
22	O	H	11-Cl	CHO	SEM	MNa++MeOH481.1	10.01(s，1H)，8.10-7.28(m，7H)，5.86(s，2H)，3.87(t，2H)，1.07(t，2H)，0.03(s，9H)
								23	S	5-Cl	H	CHO	SEM	MNa+465.1	10.02(s，1H)，7.92-7.31(m，7H)，6.09(d，1H)，5.49(d，1H)，3.87-3.67(m，2H)，1.01-0.95(m，2H)，0.03(s，9H)
24	S	H	11-Cl	CHO	SEM	MNa+465.1	10.02(s，1H)，7.98-7.36(m，7H)，6.16(d，1H)，5.36(d，1H)，3.89-3.71(m，2H)，1.08-1.02(m，2H)，0.03(s，9H)
								25	S	H	H	MAAb	(CH2)2Ph	MH+439.3	7.91-6.89(m，15H)，4.74-4.35(m，2H)，3.82(s，3H)，2.89-2.79(m，2H)

a)SEM＝(CH₃)₃SiCH₂CH₂OCH₂

b)MAA＝CH₃OCOCH＝CH

Example 3

(1-methyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -methanol (26; Table II)

To a solution of aldehyde 15(0.6mmole) in methanol (20.0ml) was added sodium borohydride (0.9mmole) with stirring at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour, and then the system was heated to room temperature and neutralized with acetic acid. Methanol was evaporated under reduced pressure. After evaporation, water was added to the residue, which was then extracted with dichloromethane. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the crystalline product was isolated.

The following compounds were prepared according to the above procedure starting from compounds 6-14:

(1-methyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -methanol;

(1-phenethyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -methanol;

(1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -methanol;

[1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

[1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

[ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

[ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

[ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

[ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol (Table II, compounds 27-35).

Example 4

3- (1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -propan-1-ol (36; Table II)

To a suspension of lithium aluminium hydride (2.9mmole) in dry diethyl ether (20.0ml) was added dropwise a solution of ester 25(0.65mmole) in dry diethyl ether (5.0 ml). The reaction mixture was stirred at room temperature for 2 hours, then excess lithium aluminum hydride was destroyed by adding diethyl ether and water. The white precipitate obtained is filtered off and subsequently freed from anhydrous Na₂SO₄Drying and evaporating the filtrate under reduced pressure. After the evaporated residue was purified by silica gel column chromatography,the oily product was isolated.

TABLE II

Compound (I)	X	Y	Z	m	R2	MS(m/z)	1H NMR(ppm)
								26	O	H	H	1	Me	MH+279.1	7.76-7.25(m，8H)，5.57(s，1H)，4.70(s，2H)，3.92(s，3H)(DMSO-d6)
27	S	H	H	1	Me	MH+295.2	7.78-7.32(m，8H)，5.53(t，1H)，4.69(d，2H)，3.81(s，3H)(DMSO-d6)
								28	O	H	H	1	(CH2)2Ph	MH+369.3	-
29	S	H	H	1	(CH2)2Ph	MH+385.4	7.83-6.95(m，13H)，4.75-4.43(m，4H)，2.87-2.72(m，2H)(CDCl3)
								30	O	H	H	1	SEMa	MH+395.0	7.86-7.31(m，8H)，5.70(t，1H)，5.63(s，2H)，4.75(d，2H)，3.69(t，2H)，0.94(t，2H)，0.03(s，9H)(DMSO-d6)
31	S	H	H	1	SEM	MH+411.0	7.91-7.32(m，8H)，5.57-5.45(m，2H)，5.07(s，2H)，4.31(br，1H)，3.71-3.45(m，2H)，1.27(t，2H)，0.03(s，9H)(CDCl3)
								32	O	5-Cl	H	1	SEM	MNa+451.3	8.06-7.18(m，7H)，5.69(br，2H)，5.43(s，2H)，3.88-3.75(m，2H)，1.05(t，2H)，0.03(s，9H)(CDCl3)
33	O	H	11-Cl	1	SEM	MNa+451.3	8.03-7.30(m，7H)，5.61(br，2H)，5.20(s，2H)，3.88-3.75(m，2H)，1.05(t，2H)，0.03(s，9H)(CDCl3)
								34	S	5-Cl	H	1	SEM	MH+445.1	-
35	S	H	11-Cl	1	SEM	MH+445.1	-
								36	S	H	H	3	(CH2)2Ph	MH+413.2	8.01-6.94(m，13H)，4.78-4.70(m，1H)，4.29-4.19(m，1H)，3.66(t，2H)，2.80-2.63(m，4H)，1.85(q，2H)(CDCl3)

a)SEM＝(CH₃)₃SiCH₂CH₂OCH₂

Example 5

a) Dimethyl- [2- (1-methyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -ethyl]Amines (I; X ═ O, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₂OCH₂，R²＝CH₃)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (2.9mmole) in 50% sodium hydroxide (2.5ml) was added a catalytic amount of benzyltriethylammonium chloride and a solution of alcohol 26(0.2mmole) in toluene (10.0 ml). The reaction mixture was heated for 3 hours with vigorous stirring and refluxed, then the system was cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with water, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the oily product was isolated.

¹H NMR(ppm，CDCl₃)：7.83-7.23(m，8H)，4.81(s，2H)，4.06(t，2H)，3.96(s，3H)，

3.17(t，2H)，2.77(s，6H)；

MS(m/z)：350.2[MH⁺].

b) Dimethyl- [3- (1-methyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -propyl]Amines (I; X ═ O, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝CH₃)

The product was obtained as an oil by reacting alcohol 26(0.2mmole) with 3-dimethylaminopropyl chloride hydrochloride (2.8 mmole);

¹H NMR(ppm，CDCl₃)：7.84-7.20(m，8H)，4.75(s，2H)，3.92(s，3H)，3.72(t，2H)，

2.99(t，2H)，2.68(s，6H)，2.13(qn，2H)；

MS(m/z)：364.3[MH⁺].

example 6

a) Dimethyl- [2- (1-methyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -ethyl]Amines (I; X ═ S, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₂OCH₂，R²＝CH₃)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (4.9mmole) in 50% sodium hydroxide (3.8ml) was added a catalytic amount of benzyltriethylammonium chloride and a solution of alcohol 27(0.35mmole) in toluene (10.0 ml). The reaction mixture was heated for 3 hours with vigorous stirring and refluxed, then the system was cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with water, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the oily product was isolated.

¹H NMR(ppm，CDCl₃)：7.89-7.32(m，8H)，4.86-4.83(m，2H)，4.02-3.96(m，2H)，

3.90(s，3H)，3.01(t，2H)，2.64(s，6H)；

MS(m/z)：366.3[MH⁺].

b) Dimethyl- [3- (1-methyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -propyl]Amines (I; X ═ S, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝CH₃)

The product was obtained as an oil by reacting alcohol 27(0.35mmole) with 3-dimethylaminopropyl chloride hydrochloride (4.9 mmole);

¹H NMR(ppm，CDCl₃)：7.89-7.28(m，8H)，4.82-4.70(m，2H)，3.84(s，3H)，3.72-3.67

(m，2H)，2.68(t，2H)，2.45(s，6H)，1.98(qn，2H)；

MS(m/z)：380.3[MH⁺].

example 7

a) Dimethyl- [2- (1-phenylethyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -ethyl]Amines (I; X ═ O, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₂OCH₂，R²＝C₆H₅CH₂CH₂)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (3.1mmole) in 50% sodium hydroxide (2.6ml) was added a catalytic amount of benzyltriethylammonium chloride and a solution of alcohol 28(0.2mmole) in toluene (10.0 ml). The reaction mixture was heated for 3 hours with vigorous stirring and refluxed, then the system was cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with water, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the oily product was isolated.

¹H NMR(ppm，CDCl₃)：7.82-6.99(m，13H)，4.61(t，2H)，4.43(s，2H)，3.99(t，2H)，

3.23(t，2H)，2.97(t，2H)，2.84(s，6H)；

MS(m/z)：440.3[MH⁺].

b) Dimethyl- [3- (1-methyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -propyl]Amines (I; X ═ O, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝CH₃)

The product was obtained as an oil by reacting alcohol 28(0.2mmole) with 3-dimethylaminopropyl chloride hydrochloride (2.9 mmole);

¹H NMR(ppm，CDCl₃)：7.84-7.02(m，13H)，4.57(t，2H)，4.45(s，2H)，3.66(t，2H)，

3.09(t，2H)，2.98(t，2H)，2.75(s，6H)，2.21-2.16(m，2H)；

MS(m/z)：454.3[MH⁺].

example 8

a) Dimethyl- [2- (1-phenylethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -ethyl]Amines (I; X ═ S, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₂OCH₂，R²＝C₆H₅CH₂CH₂)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (4.2mmole) in 50% sodium hydroxide (3.3ml) was added a catalytic amount of benzyltriethylammonium chloride and a solution of alcohol 29(0.3mmole) in toluene (10.0 ml). The reaction mixture was heated for 3 hours with vigorous stirring and refluxed, then the system was cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with water, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the oily product was isolated.

¹H NMR(ppm，CDCl₃)：7.86-6.95(m，13H)，4.75-4.22(m，4H)，3.83-3.68(m，2H)，

2.92-2.67(m，4H)，2.55(s，6H)；

MS(m/z)：456.3[MH⁺].

b) Dimethyl- [3- (1-methyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -propyl]-amines(I；X＝S，Y＝Z＝H，m＝1，R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝C₆H₅CH₂CH₂)

The product was obtained as an oil by reacting alcohol 29(0.5mmole) with 3-dimethylaminopropyl chloride hydrochloride (7.2 mmole);

¹H NMR(ppm，CDCl₃)：7.87-6.98(m，13H)，4.64-4.18(m，4H)，3.60(s，2H)，2.77-

2.74(m，4H)，2.49(s，6H)，1.99(m，2H)；

MS(m/z)：470.2[MH⁺].

example 9

a) Dimethyl- {2- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]-ethyl } -amine (I; X ═ O, Y ═ Z ═ H, m ═ 1, R ═ R¹＝(CH₃)₂N(CH₂)₂OCH₂，R²＝(CH₃)₃Si(CH₂)₂OCH₂) Dimethyl- [2- (1H-8-oxa-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -ethyl]Amines (I; X ═ O, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₂OCH₂，R²＝H)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (7.5mmole) in 50% sodium hydroxide (5.9ml) was added a catalytic amount of benzyltriethylammonium chloride and a solution of alcohol 30(0.53mmole) in toluene (8 ml). The reaction mixture was heated for 3 hours with vigorous stirring and refluxed, then the system was cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with water, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by column chromatography on silica gel, dimethyl- {2- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-mine was isolatedHetero-dibenzo [ e, h ]]Azulen-2-ylmethoxy]-ethyl } -amine, product in oily form;

¹H NMR(ppm，CDCl₃)：7.84-7.23(m，8H)，5.52(s，2H)，4.86(s，2H)，3.83(m，2H)，

3.70(t，2H)，3.01(m，2H)，2.65(s，6H)，0.99(t，2H)，0.03(s，

9H)；

MS(m/z)：466.3[MH⁺].

to dimethyl- {2- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]To a solution of-ethyl } -amine (0.34mmole) in methanol (9.0ml) was slowly added a 0.5M solution of hydrochloric acid in methanol (3.3 ml). The reaction mixture was heated at reflux for 3 hours, then the system was cooled to room temperature, neutralized with saturated aqueous sodium bicarbonate solution, diluted with water and extracted with dichloromethane. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification by column chromatography on silica gel, dimethyl- [2- (1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] is isolated]Azulen-2-ylmethoxy) -ethyl]-an amine in the form of an oily product;

¹H NMR(ppm，CDCl₃)：8.15-7.17(m，8H)，4.86(s，2H)，3.89(t，2H)，3.12(t，2H)，

2.75(s，6H)；

MS(m/z)：336.0[MH⁺].

b) dimethyl- {3- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H]Azulene-ylmethoxy group]-propyl } -amine (I; X ═ O, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝(CH₃)₃Si(CH₂)₂OCH₂)

Dimethyl- [3- (1H-8-oxa-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -propyl]Amines (I; X ═ O, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝H)

Dimethyl- {3- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-ylmethoxy ] -propyl } -amine was obtained as an oily product by reacting alcohol 30(0.49mmole) with 3-dimethylaminopropyl chloride-hydrochloride (6.9 mmole);

¹H NMR(ppm，CDCl₃)：7.84-7.23(m，8H)，5.49(s，2H)，4.80(s，2H)，3.72-3.67(m，

4H)，2.81(t，2H)，2.55(s，6H)，2.03(qn，2H)，0.99(t，2H)，0.03

(s，9H)；

MS(m/z)：480.3[MH⁺].

after removal of the N-protecting group and purification by silica gel column chromatography, dimethyl- [3- (1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -amine is obtained as oily product;

¹H NMR(ppm，CDCl₃)：12.32(s，1H)，8.17-7.29(m，8H)，5.20(s，2H)，3.92(m，2H)，

3.29(m，2H)，2.92(s，6H)，2.16(m，2H)；

MS(m/z)：350.1[MH⁺].

c)3- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]Propylamine (I; X ═ O, Y ═ Z ═ H, m ═ 1, R¹＝H₂N(CH₂)₃OCH₂，R²＝(CH₃)₃Si(CH₂)₂OCH₂)

3- (1H-g-oxa-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -propylamine (I; x ═ O, Y ═ Z ═ H, m ═ 1, R¹＝H₂N(CH₂)₃OCH₂，R²＝H)

3- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] -azulen-ylmethoxy ] -propylamine was obtained as an oily product by reacting alcohol 30(0.49mmole) with 3-methylaminopropyl chloro-hydrochloride (10.0 mmole);

MS(m/z)：452.2[MH⁺].

after removal of the N-protecting group and purification by silica gel column chromatography, 3- (1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propylamine was obtained as an oily product;

MS(m/z)：322.1[MH⁺].

example 10

a) Dimethyl- {2-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]-ethyl } -amine (I; X ═ S, Y ═ Z ═ H, m ═ 1, R ═ R¹＝(CH₃)₂N(CH₂)₂OCH₂，R²＝(CH₃)₃Si(CH₂)₂OCH₂)

Dimethyl- [2- (1H-8-thia-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -ethyl]Amines (I; X ═ S, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₂OCH₂，R²＝H)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (7.6mmole) in 50% sodium hydroxide (6.0ml) was added a catalytic amount of benzyltriethylammonium chloride and a solution of alcohol 31(0.55mmole) in toluene (8.0 ml). The reaction is stirred vigorouslyThe mixture was heated for 3 hours and refluxed, then the system was cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with water, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography dimethyl- {2- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] was isolated]Azulen-2-ylmethoxy]-ethyl } -amine, product in oily form;

¹H NMR(ppm，CDCl₃)：8.15-7.31(m，8H)，5.98-5.84(m，2H)，5.57-5.35(m，2H)，

4.41-4.32(m，2H)，3.49-3.41(m，4H)，2.97(s，6H)，0.88(t，

2H)，0.03(s，9H)；

MS(m/z)：482.2[MH⁺].

to dimethyl- {2- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H [ ]]Azulen-2-ylmethoxy]To a solution of-ethyl } -amine (0.32mmole) in methanol (7.0ml) was slowly added a 0.5M solution of hydrochloric acid in methanol (3.2 ml). The reaction mixture was heated at reflux for 3 hours, then the system was cooled to room temperature, neutralized with saturated aqueous sodium bicarbonate solution, diluted with water and extracted with dichloromethane. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification by column chromatography on silica gel, dimethyl- [2- (1H-8-thia-1, 3-diaza-dibenzo [ e, H ] is isolated]Azulen-2-ylmethoxy) -ethyl]-an amine in the form of an oily product;

¹H NMR(ppm，CDCl₃)：8.01-7.37(m，8H)，5.34-5.30(m，2H)，4.11(m，2H)，3.42(m，

2H)，2.94(m，6H)；

MS(m/z)：352.3[MH⁺].

b) dimethyl- {3- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H]Azulene-ylmethoxy-propyl]Amines (I; X ═ S, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝(CH₃)₃Si(CH₂)₂OCH₂)

Dimethyl- [3- (1H-8-thia-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -propyl]Amines (I; X ═ O, Y ═ Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝H)

Dimethyl- {3- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -propyl } -amine was obtained as an oily product by reacting alcohol 31(0.58mmole) with 3-dimethylaminopropyl chloride-hydrochloride (8.1 mmole);

¹H NMR(ppm，CDCl₃)：7.95-7.29(m，8H)，5.60-5.49(m，2H)，4.98-4.87(m，2H)，

3.83-3.82(m，2H)，3.68-3.39(m，2H)，3.21-3.18(m，2H)，2.82

(s，6H)，2.26(m，2H)，0.91(t，2H)，0.03(s，9H)；

MS(m/z)：496.4[MH⁺].

after removal of the N-protecting group and purification by silica gel column chromatography, dimethyl- [3- (1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -amine is obtained as oily product;

¹H NMR(ppm，CDCl₃)：12.00(bs，1H)，7.97-7.39(m，8H)，5.10(m，2H)，3.86(m，

2H)，3.22(m，2H)，2.88(m，6H)，2.13(m，2H)；

MS(m/z)：366.1[MH⁺].

example 11

a) {3- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]-propyl } -dimethyl-amine (I; X ═ O, Y ═ 5 ═ Cl, Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝(CH₃)₃Si(CH₂)₂OCH₂)

[3- (5-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ]]Azulen-2-ylmethoxy) -propyl]-dimethyl-amine (I; X ═ O, Y ═ 5-Cl, Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝H)

To a solution of 2-dimethylaminopropyl chloride-hydrochloride (2.1mmole) in 50% sodium hydroxide (1.7ml) was added a catalytic amount of benzyltriethylammonium chloride and a solution of alcohol 32(0.15mmole) in toluene (5.0 ml). The reaction mixture was heated for 3 hours with vigorous stirring and refluxed, then the system was cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with water, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, {3- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] is isolated]Azulen-2-ylmethoxy]-propyl } -dimethyl-amine, product in oily form;

MS(m/z)：514.0[MH⁺].

after removal of the N-protecting group and purification by silica gel column chromatography, {3- [ 5-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -dimethyl-amine is obtained as oily product;

¹H NMR(ppm，CDCl₃)：8.17-7.16(m，7H)，4.76(s，2H)，3.76(t，2H)，3.08(t，2H)，

2.76(s，6H)，2.06(qn，2H)；

MS(m/z)：384.1[MH⁺].

b)3- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]Propylamine (I; X ═ O, Y ═ 5-Cl, Z ═ H, m ═ 1, R ═ H¹＝H₂N(CH₂)₃OCH₂，R²＝(CH₃)₃Si(CH₂)₂OCH₂)

3- (5-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H)]Azulen-2-ylmethoxy) -propylamine (I; x ═ O, Y ═ 5-Cl, Z ═ H, m ═ 1, R¹＝H₂N(CH₂)₃OCH₂，R²＝H)

3- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] is obtained by reacting alcohol 32(0.46mmole) with 3-aminopropylchloro-hydrochloride (6.4mmole)]Azulen-2-ylmethoxy]-propylamine in the form of an oily product; MS (m/z): 486.1[ MH⁺].

After removal of the N-protecting group and purification by silica gel column chromatography, 3- [ 5-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -propylamine was obtained as an oily product;

MS(m/z)：356.2[MH⁺].

example 12

a) {2- [ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]-ethyl } -dimethyl-amine (I; X ═ O, Y ═ H, Z ═ 11-Cl, m ═ 1, R¹＝(CH₃)₂N(CH₂)₂OCH₂，R＝(CH₃)₃Si(CH₂)₂OCH₂)

[2- (11-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ]]Azulen-2-ylmethoxy) -ethyl]-dimethyl-amine (I; X ═ O, Y ═ H, Z ═ 11-Cl, m ═ 1, R¹＝(CH₃)₂N(CH₂)₂OCH₂，R²＝H)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (3.6mmole) in 50% sodium hydroxide (2.9ml) was added a catalytic amount of benzyltriethylammonium chloride and a solution of alcohol 33(0.26mmole) in toluene (6 ml). The reaction mixture was heated and refluxed for 3 hours with vigorous stirring, then the system was cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with water, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, {2- [ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] is isolated]Azulen-2-ylmethoxy]-ethyl } -dimethyl-amine, product in oily form;

MS(m/z)：499.9[MH⁺].

to {2- [ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]To a solution of-ethyl } -dimethyl-amine (0.13mmole) in methanol (3.0ml) was slowly added a 0.5M solution of hydrochloric acid in methanol (1.3 ml). The reaction mixture was heated at reflux for 3 hours, then the system was cooled to room temperature, neutralized with saturated aqueous sodium bicarbonate solution, diluted with water and extracted with dichloromethane. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. Purifying by silica gel column chromatography, and separating [2- (11-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ]]Azulen-2-ylmethoxy) -ethyl]-dimethyl-amine in the form of an oily product;

¹H NMR(ppm，CDCl₃)：8.12-7.15(m，7H)，4.86(s，2H)，3.88(t，2H)，3.06(t，2H)，

2.70(s，6H)；

MS(m/z)：370.1[MH⁺].

b) {3- [ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]-propyl } -dimethyl-amine (I; X ═ O, Y ═ H, Z ═ 11-Cl, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝(CH₃)₃Si(CH₂)₂OCH₂)

[3- (11-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ]]Azulen-2-ylmethoxy) -propyl]-dimethyl-amine (I; X ═ O, Y ═ H, Z ═ 11-Cl, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝H)

By reacting alcohol 33(0.15mmole) with 3-dimethylaminopropyl chloro-hydrochloride (2.1mmole) to give {3- [ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -propyl } -dimethyl-amine as an oily product;

MS(m/z)：514.2[MH⁺].

after removal of the N-protecting group and purification by silica gel column chromatography, [3- (11-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -dimethyl-amine is obtained as oily product;

MS(m/z)：384.1[MH⁺].

example 13

a) {2- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]-ethyl } -dimethyl-amine (I; X ═ S, Y ═ H, Z ═ 5-Cl, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝(CH₃)₃Si(CH₂)₂OCH₂)

[2- (5-chloro-1H-8-thia-1, 3-diaza-dibenzo [ e, H ]]Azulen-2-ylmethoxy) -ethyl]-dimethyl-amine (I; X ═ S, Y ═ 5-Cl, Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝H)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (4.8mmole) in 50% sodium hydroxide (3.8ml) was added a catalytic amount of benzyltriethylammonium chloride and a solution of alcohol 34(0.35mmole) in toluene (10.0 ml). The reaction mixture was heated and refluxed for 3 hours with vigorous stirring, then the system was cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with water, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, bis {2- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] was isolated]Azulen-2-ylmethoxy]-ethyl } -dimethyl-amine, product in oily form;

MS(m/z)：516.5[MH⁺].

to {2- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H]Azulen-2-ylmethoxy]To a solution of-ethyl } -dimethyl-amine (0.21mmole) in methanol (6.0ml) was slowly added a 0.5M solution of hydrochloric acid in methanol (2.0 ml). The reaction mixture was heated at reflux for 3 hours, then the system was cooled to room temperature, neutralized with saturated aqueous sodium bicarbonate solution, diluted with water and extracted with dichloromethane. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. Purifying by silica gel column chromatography to obtain [2- (5-chloro-1H-8-oxa-1, 3-aza-dibenzo [ e, H ]]Azulen-2-ylmethoxy) -ethyl]-dimethyl-amine in the form of an oily product;

MS(m/z)：386.1[MH⁺].

b) {3- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-bisBenzo [ e, h)]Azulen-2-ylmethoxy]-propyl } -dimethyl-amine (I; X ═ S, Y ═ 5-Cl, Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝(CH₃)₃Si(CH₂)₂OCH₂)

[3- (5-chloro-1H-8-thia-1, 3-diaza-dibenzo [ e, H ]]Azulen-2-ylmethoxy) -propyl]-dimethyl-amine (I; X ═ O, Y ═ 5-Cl, Z ═ H, m ═ 1, R¹＝(CH₃)₂N(CH₂)₃OCH₂，R²＝H)

By reacting alcohol 34(0.34mmole) with 3-dimethylaminopropyl chloro-hydrochloride (4.8mmole) to give {3- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -propyl } -dimethyl-amine as an oily product;

MS(m/z)：530.2[MH⁺].

after removal of the N-protecting group and purification by silica gel column chromatography, [3- (5-chloro-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -dimethyl-amine is obtained as oily product;

MS(m/z)：400.0[MH⁺].

example 14

Dimethyl- {3- [3- (1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H)]Azulen-2-yl) -propoxy]-propyl } -amine (I; X ═ S, Y ═ Z ═ H, m ═ 3, R¹＝(CH₃)₂N(CH₂)₃O(CH₂)₂CH₂，R²＝C₆H₅CH₂CH₂)

To a solution of 2-dimethylaminopropyl chloride-hydrochloride (2.6mmole) in 50% sodium hydroxide (2.2ml) was added a catalytic amount of benzyltriethylammonium chloride and a solution of alcohol 36(0.19mmole) in toluene (5.0 ml). The reaction mixture was heated and refluxed for 5 hours with vigorous stirring, and then the system was heatedCooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with water, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, an oily product was obtained;

MS(m/z)：498.4[MH⁺].

preparation of starting Compounds

Method A

1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene (1; Table III)

To dibenzo [ b, f)]To a solution of oxepin-10, 11-dione (9.6mmole) in acetic acid (30.0ml) were added ammonium acetate (96.0mmole) and paraformaldehyde (11.5 mmole). The reaction mixture was heated and refluxed for 4 hours with stirring, then the system was cooled to room temperature, diluted with water, neutralized with ammonium hydroxide and extracted with ethyl acetate. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the crystalline product was isolated.

According to the above process, the following compounds are used as starting materials:

dibenzo [ b, f ] thiepin-10, 11-dione;

2-chloro-dibenzo [ b, f ] oxepin-10, 11-dione;

2-chloro-dibenzo [ b, f ] thiacycloheptene-10, 11-dione;

the following compounds were prepared:

1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene;

5-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene;

5-chloro-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulenes

(Table III, Compounds 2-4).

Method B

1-methyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene (5; Table III)

To a solution of compound 1(2.8mmole) in dry tetrahydrofuran (20.0ml) was added a suspension of 60% sodium hydride in mineral oil (8.4mmole) at 0 ℃ with stirring. The reaction mixture was stirred at 0 ℃ for 30 minutes, then methyl iodide (4.2mmole) was added thereto and the reaction mixture was heated with stirring and refluxed for another 5 hours. The system was then cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the crystalline product was isolated.

1-methyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene (6; Table III) was prepared from compound 2 according to the above procedure.

Method C

1-phenethyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene (7; Table III)

To a solution of compound 1(2.6mmole) in dry tetrahydrofuran (20.0ml) was added a suspension of 60% sodium hydride in mineral oil (8.0mmole) at 0 ℃ with stirring. The reaction mixture was stirred at 0 ℃ for 30 minutes, then 2-phenethyl bromide (5.2mmole) and a catalytic amount of tetra-n-butylammonium iodide were added thereto and the reaction mixture was heated with stirring and refluxed for another 5 hours. The system was then cooled to room temperature, diluted with water and extracted with dichloromethane. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the crystalline product was isolated.

1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene (8; Table III) was prepared from compound 2 according to the above procedure.

Method D

1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene (9; Table III)

To a solution of compound 1(1.1mmole) in dry tetrahydrofuran (7.0ml) was added a suspension of 60% sodium hydride in mineral oil (3.2mmole) at 0 ℃ with stirring. The reaction mixture was stirred at 0 ℃ for 30 minutes, then 2- (trimethylsilyl) ethoxymethyl-chloride (1.1mmole) was added thereto and the reaction mixture was stirred at room temperature for another 3 hours. The system was diluted with water and extracted with dichloromethane. Washing the organic extract with aqueous sodium chloride solution, and adding anhydrous Na₂SO₄Dried and evaporated under reduced pressure. After purification of the evaporated residue by silica gel column chromatography, the crystalline product was isolated.

1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene (10; Table III) was prepared from compound 2 according to the above procedure.

1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene (10; Table III) was prepared from compound 2 as starting material according to the above procedure.

Preparation of isomers starting from compound 3:

5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene;

11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene;

and the isomer was prepared from compound 4 as starting material:

5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene;

11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-g-thia-1, 3-diaza-dibenzo [ e, H ] azulene (table III, compounds 1-14).

TABLE III

Compound (I)	X	Y	Z	R2	MS(m/z)	1H NMR(ppm)
							1	O	H	H	H	MH+235.4	12.92(s，1H)，7.96(s，1H)，7.65-7.26(m，8H)(DMSO-d6)
2	S	H	H	H	MH+250.8	12.91(s，1H)，7.99(s，1H)，7.84-7.35(m，8H)(DMSO-d6)
							3	O	5-Cl	H	H	MH+268.8	13.03(s，1H)，8.00(s，1H)，7.75-7.29(m，7H)(DMSO-d6)
4	S	5-Cl	H	H	MH+284.9	13.06(s，1H)，8.04(s，1H)，7.77-7.42(m，7H)(DMSO-d6)
							5	O	H	H	Me	MH+249.2	7.95(s，1H)，7.91-7.21(m，8H)，3.95(s，3H)(CDCl3)
6	S	H	H	Me	MH+265.1	7.94-7.28(m，9H)，3.88(s，3H)(CDCl3)
							7	O	H	H	(CH2)2Ph	MH+339.3	7.96-7.09(m，14H)，4.55(t，2H)，3.11(t，2H)(CDCl3)
8	S	H	H	(CH2)2Ph	MH+355.3	8.25(s，1H)，7.98-7.03(m，13H)，4.73-4.44(m，2H)，2.98(t，2H)(CDCl3)
							9	O	H	H	SEMa	MH+365.2	8.38(s，1H)，7.92-7.20(m，8H)，5.50(s，2H)，3.77(t，2H)，0.99(t，2H)，0.03(s，9H)(CDCl3)
10	S	H	H	SEM	MH+381.3	8.57(s，1H)，8.01-7.37(m，8H)，5.62-5.38(m，2H)，3.92-3.66(m，2H)，1.06-0.95(m，2H)，0.03(s，9H)(CDCl3)
							11	O	5-Cl	H	SEM	MH+399.1	8.49(s，1H)，8.37-7.21(m，7H)，5.55(s，2H)，3.82(t，2H)，1.04(t，2H)，0.03(s，9H)(CDCl3)
12	O	H	11-Cl	SEM	MH+399.1	8.48(s，1H)，7.97-7.27(m，7H)，5.53(s，2H)，3.83(t，2H)，1.07(t，2H)，0.03(s，9H)(CDCl3)
							13	S	5-Cl	H	SEM	MH+415.0	8.36(s，1H)，8.00-7.33(m，7H)，5.59-5.48(m，2H)，3.93-3.84(m，1H)，3.75-3.66(m，1H)，1.08-1.03(m，2H)，0.03(s，9H)(CDCl3)
14	S	H	11-Cl	SEM	MH+414.9	8.40(s，1H)，8.07-7，33(m，7H)，5.67-5.49(m，2H)，3.93-3.81(m，2H)，1.10(m，2H)，0.03(s，9H)(CDCl3)

a)SEM＝(CH₃)₃SiCH₂CH₂OCH₂

Claims (14)

1. A compound of formula I:

wherein

X may be CH₂Or heteroatoms such as O, S, S (═ O), S (═ O)₂Or NR^aWherein R is^aIs hydrogen or a protecting group;

y and Z independently of each other represent one or more of the same or different andis intended to be a substituent attached to a carbon atom and may be halogen, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, halo-C₁-C₄Alkyl, hydroxy, C₁-C₄Alkoxy, trifluoromethoxy, C₁-C₄Alkanoyl, amino-C₁-C₄Alkyl, N- (C)₁-C₄Alkyl) amino, N-di (C)₁-C₄Alkyl) amino, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, carboxy, C₁-C₄Alkoxycarbonyl, cyano, nitro;

R¹can be halogen, hydroxyl, C₁-C₇Alkoxy, aryloxy, amino, N- (C)₁-C₇Alkyl) amino, N-di (C)₁-C₇Alkyl) amino, (C)₁-C₇Alkyl) amino, amino-C₁-C₇Alkoxy radical, C₁-C₇Alkanoyl, aroyl, C₁-C₇Alkanoyloxy, carboxy, optionally substituted C₁-C₇Alkoxycarbonyl or aryloxycarbonyl, carbamoyl, N- (C)₁-C₇Alkyl) carbamoyl, N-di (C)₁-C₇Alkyl) carbamoyl, cyano, nitro

Or a substituent of formula II:

wherein

R³And R⁴Can be hydrogen and C simultaneously or independently of each other₁-C₄-alkyl, aryl or together with N have the meaning of optionally substituted heterocycle or heteroaryl;

m represents an integer of 1 to 3;

n represents an integer of 0 to 3;

Q₁and Q₂Independently of one another, represents oxygen, sulfur or the following groups:

-C≡C-

wherein the substituents are

y₁And y₂May be independently of one another hydrogen, halogen, optionally substituted C₁-C₄Alkyl or aryl, hydroxy, C₁-C₄Alkoxy radical, C₁-C₄Alkanoyl, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, cyano, nitro or together form a carbonyl or imino group;

R²with hydrogen, optionally substituted C₁-C₇Alkyl or aryl or protective group meanings: formyl radical, C₁-C₇Alkanoyl radical, C₁-C₇Alkoxycarbonyl, arylalkoxycarbonyl, aroyl, arylalkyl, C₁-C₇An alkylsilyl group.

2. A compound according to claim 1, wherein X has the meaning of S or O.

3. A compound according to claim 2, wherein Y and Z have the meaning of H or Cl.

4. The compound of claim 3, wherein R¹Having CHO or CH₃Och ═ CH, and R²With H, CH₃、C₆H₅CH₂CH₂Or (CH)₃)₃SiCH₂CH₂OCH₂The meaning of (a).

5. The compound of claim 3, wherein R¹Has (CH)₂)_mOH, andand R is²With H, CH₃、C₆H₅CH₂CH₂Or (CH)₃)₃SiCH₂CH₂OCH₂The meaning of (a).

6. A compound according to claim 5, wherein the symbol m has the meaning of 1 or 3.

7. The compound of claim 3, wherein R¹Has the meaning of the general formula II.

8. A compound as claimed in claim 7, wherein the symbol m has the meaning 1 or 3, Q₁Has the meaning of O, n has the meaning of 1 or 2, Q₂Having a CH₂Meaning of (A), R²With H, CH₃、C₆H₅CH₂CH₂Or (CH)₃)₃SiCH₂CH₂OCH₂And R is³And R⁴Having H and/or CH₃The meaning of (a).

9. The selected compound of claim 4:

1-methyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

1-methyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

1-phenethyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulene-2-aldehyde;

3- (1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -acrylic acid methyl ester.

10. The selected compound of claim 6:

(1-methyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -methanol;

(1-methyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -methanol;

(1-phenethyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -methanol;

(1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -methanol;

[1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

[1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

[ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

[ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

[ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

[ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl ] -methanol;

3- (1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -propan-1-ol.

11. Selected from the compounds and salts of claim 8:

dimethyl- [2- (1-methyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -ethyl ] -amine;

dimethyl- [3- (1-methyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -amine;

dimethyl- [2- (1-methyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -ethyl ] -amine;

dimethyl- [3- (1-methyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -amine;

dimethyl- [2- (1-phenethyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -ethyl ] -amine;

dimethyl- [3- (1-phenethyl-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -amine;

dimethyl- [2- (1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -ethyl ] -amine;

dimethyl- [3- (1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -amine;

dimethyl- {2- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -ethyl } -amine;

dimethyl- [2- (1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -ethyl ] -amine;

dimethyl- {3- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-ylmethoxy ] -propyl } -amine;

dimethyl- [3- (1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -amine;

3- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy- ] propylamine;

3- (1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propylamine;

dimethyl- {2- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -ethyl } -amine;

dimethyl- [2- (1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -ethyl ] -amine;

dimethyl- {3- [1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -propyl } -amine;

dimethyl- [3- (1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -amine;

{3- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -propyl } -dimethyl-amine;

[3- (5-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -dimethyl-amine;

3- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -propylamine;

3- (5-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propylamine;

{2- [ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -ethyl } -dimethyl-amine;

[2- (11-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -ethyl ] -dimethyl-amine;

{3- [ 11-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -propyl } -dimethyl-amine;

[3- (11-chloro-1H-8-oxa-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -dimethyl-amine;

{2- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -ethyl-dimethyl-amine;

[2- (5-chloro-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -ethyl ] -dimethyl-amine;

{3- [ 5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy ] -propyl } -dimethyl-amine;

[3- (5-chloro-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-ylmethoxy) -propyl ] -dimethyl-amine;

dimethyl- {3- [3- (1-phenethyl-1H-8-thia-1, 3-diaza-dibenzo [ e, H ] azulen-2-yl) -propoxy ] -propyl } -amine.

12. A process for the preparation of compounds of formula I:

wherein

X may be CH₂Or heteroatoms such as O, S, S (═ O), S (═ O)₂Or NR^aWherein R is^aIs hydrogen or a protecting group;

y and Z independently of one another represent one or more identical or different substituents attached to any available carbon atom and may be halogen, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, halo-C₁-C₄Alkyl, hydroxy, C₁-C₄Alkoxy, trifluoromethoxy, C₁-C₄Alkanoyl, amino-C₁-C₄Alkyl, N- (C)₁-C₄Alkyl) amino, N-di (C)₁-C₄Alkyl) amino, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, carboxy, C₁-C₄Alkoxycarbonyl, cyano, nitro;

R¹can be halogen, hydroxyl, C₁-C₇Alkoxy, aryloxy, amino, N- (C)₁-C₇Alkyl) amino, N-di (C)₁-C₇Alkyl) amino, (C)₁-C₇Alkyl) amino, amino-C₁-C₇Alkoxy radical, C₁-C₇Alkanoyl, aroyl, C₁-C₇Alkanoyloxy, carboxy, optionally substituted C₁-C₇Alkoxycarbonyl or aryloxycarbonyl, carbamoyl, N- (C)₁-C₇Alkyl) carbamoyl, N-di (C)₁-C₇Alkyl) carbamoyl, cyano, nitro

Or a substituent of formula II:

wherein

R³And R⁴Can be hydrogen and C simultaneously or independently of each other₁-C₄-alkyl, aryl or together with N have the meaning of optionally substituted heterocycle or heteroaryl;

m represents an integer of 1 to 3;

n represents an integer of 0 to 3;

Q₁and Q₂Independently of one another, represents oxygen, sulfur or the following groups:

-C≡C-

wherein the substituents are

y₁And y₂May be independently of one another hydrogen, halogen, optionally substituted C₁-C₄Alkyl or aryl, hydroxy, C₁-C₄Alkoxy radical, C₁-C₄Alkanoyl, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, cyano, nitro or together form a carbonyl or imino group;

R²with hydrogen, optionally substituted C₁-C₇Alkyl or aryl or protective group meanings: formyl radicalsBase, C₁-C₇Alkanoyl radical, C₁-C₇Alkoxycarbonyl, arylalkoxycarbonyl, aroyl, arylalkyl, C₁-C₇An alkylsilyl group;

the preparation method is characterized by comprising the following steps:

a) for compounds of the formula I, in which R is¹Having the meaning of CHO, formylating a compound of the general formula III:

b) for compounds of the formula I, in which Q₁Having the meaning of-O-, reacting an alcohol of the formula IV with a compound of the formula V,

wherein the structural formula of formula IV is as follows:

wherein the formula of formula V is as follows:

wherein L is¹Having the meaning of a leaving group;

c) for compounds of the formula I, in which Q₁Has the meaning of-O-, -NH-, -S-or-C ≡ C-,

reacting a compound of formula IVa with a compound of formula Va,

wherein the formula of formula IVa is as follows:

wherein L has the meaning of a leaving group;

wherein the formula of formula Va is as follows:

d) with respect to the compounds of the general formula IIn the formula, Q₁Having the meaning of-O-, -NH-or-S-, reacting a compound of the formula IVb with a compound of the formula V,

wherein the formula of formula IVb is as follows:

in the compounds of the formula V, L¹Having the meaning of a leaving group;

e) for compounds of the formula I, in which Q₁Has the meaning of-C ═ C-,

reacting a compound of formula IVb, in which Q is Q, with a phosphonium ylide₁Has the meaning of carbonyl.

13. Use of compounds of general formula I according to claims 4 and 5 as intermediates for the preparation of the novel compounds 1, 3-diaza-dibenzoazulene having anti-inflammatory action.

14. The use of compounds of general formula I according to claim 7 for the treatment and prophylaxis of any pathological condition or disease induced by an excessive production of unregulated cytokines or inflammatory mediators in such a way that a non-toxic dose of a suitable pharmaceutical preparation can be administered orally, parenterally or topically.